Does Modifying Dietary Lipids Influence the Progression of Renal Failure?

RENAL DYSFUNCTION

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DOES MODIFYING DIETARY LIPIDS INFLUENCE THE PROGRESSION OF RENAL FAILURE? Scott A. Brown, VMD, PhD, Cathy A. Brown, VMD, PhD, Wayne A. Crowell, DVM, PhD, Jeanne A. Barsanti, DVM, MS, and Delmar R. Finco, DVM, PhD

Chronic renal disease frequently progresses to end-stage renal failure in dogs and cats. 12• 23 Consequently, therapy to slow the rate of progression of renal disease is particularly important. A variety of factors appear responsible for the progressive nature of renal injury in animals. Some of these factors might be controlled by changes in dietary fatty acid composition. These include (1) the triad of glomerular hyperfiltration, hypertension, and hypertrophy, (2) systemic hypertension, (3) hyperlipidemia, and (4) renal injury induced by platelet aggregation or inflammation. 1• 3• 13• 21 GLOMERULAR HYPERFILTRATION, HYPERTENSION, AND HYPERTROPHY AND PROGRESSIVE RENAL INJURY

One or more factors associated with glomerular adaptations to renal disease may perpetuate renal injury. 3 In the kidneys of affected animals, some nephrons survive while others perish. The surviving, or remnant, nephrons became larger and exhibit increases in glomerular capillary pressure and filtration rate. These changes are referred to as glomerular hypertrophy, glomerular hypertension, This work was supported by the Morris Animal Foundation. From the Department of Physiology & Pharmacology (SAB, DRF), the Diagnostic Laboratory (CAB), the Department of Pathology (WAC), and the Department of Small Animal Medicine GAB), College of Veterinary Medicine, University of Georgia, Athens, Georgia VETERINARY CLINICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE VOLUME 26 • NUMBER 6 • NOVEMBER 1996

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and glomerular hyperfiltration, respectively. Brenner and colleagues3 proposed that these changes in nephron structure and function were maladaptive, causing renal injury (Fig. 1). Recently, several studies have addressed these issues in dogs and cats. In particular, studies have shown that, in both dogs and cats with renal insufficiency, glomerular hypertension and hypertrophy are observed. 6 • 9 Because these changes in remnant nephron structure and function are apparently an inherent property of nephrons after substantial renal injury in animals, some aspects of Brenner's hypothesis apply to species of interest to veterinarians. Recently, in an experimental model of diabetic nephropathy, chronic administration of an angiotensin converting enzyme inhibitor reduced glomerular capillary hypertension and hypertrophy. 8 This response was associated with beneficial limitation of the degree of mesangial expansion and glomerulosclerosis, markers

CHRONIC RENAL DISEASE

,, RENAL ADAPTATIONS

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GLOMERULAR

GLOMERULAR

GLOMERULAR

HYPERFILTRATION

HYPERTENSION

HYPERTROPHY

I

I r HEMODYNAMICALLY MEDIATED RENAL INJURY

~ PROGRESSIVE RENAL FAILURE

Figure 1. The hemodynamic theory of progressive renal injury. According to proponents of this hypothesis, glomerular adaptations to renal disease, that include increases in glomerular filtration rate, glomerular pressure, and glomerular size, are maladaptive and lead to renal injury and self-perpetuating progressive renal failure.

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of diabetic nephropathy. 14 Because of similarities in adaptive changes in diabetes and remnant kidney, the response to reducing the extent of glomerular hypertension and hypertrophy in nondiabetic dogs and cats with renal disease might also be favorable. If so, efforts to limit these glomerular "maladaptations" might prove beneficial in dogs and cats with renal disease. DIETARY FATTY ACID SUPPLEMENTATION AND GLOMERULAR MALADAPTATIONS

The type of dietary fatty acid ingested by affected animals may alter renal adaptations to disease .I· 21· 26 Fatty acids are generally categorized on the basis of number and location of carbon-carbon double bonds. Dietary fatty acids that contain no double bonds, such as palmitic acid, are referred to as saturated fatty acids. Animal fats, which contain predominantly saturated fatty acids, are often incorporated into canine and feline diets because of availability and palatability. In contrast, plant sources of fat contain high proportions of the polyunsaturated fatty acid linoleic acid. Linoleic acid is referred to as an omega-6 polyunsaturated fatty acid (w-6 PUFA) because the first carbon-carbon double bond occurs at the sixth carbon from the methyl group. In most mammals, including people and dogs, linoleic acid is readily converted to arachidonic acid, the immediate precursor of eicosanoids (prostaglandins and thromboxanes). However, in cats the conversion of linoleic to arachidonic acid is limited and both are essential dietary fatty acids in this species. 19· 20 An alternative source of PUFA is menhaden oil derived from fish feeding on plankton. These oils are rich in eicosapentaenoic acid and docosahexaenoic acid, which are omega-3 PUFA (w-3 PUFA). Thus substantially different chemical forms of fatty acids are obtained when pet foods are supplemented with lipids obtained from animal fat, plant oil, or menhaden oil. These dietary fatty acids may affect renal function through effects on renal eicosanoid metabolism. Eicosanoids are compounds derived from PUF A within cell membranes and include prostaglandins, prostacyclin, and thromboxanes.1· 4• 16· 26 The usual precursor for eicosanoids is arachidonic acid. In dogs, people, al).d rats, arachidonic acid is derived from the PUFA linoleic acid, which comprises 50% to 80% of plant oils. The principal eicosanoids (Fig. 2) derived from the w-6 polyunsaturated fatty acid arachidonic acid, include prostaglandin E2 (PGE 2), prostacyclin (PGI2), and thromboxane A2 (TxA2). The vasodilatory eicosanoids, PGE2 and PGI2, increase renal blood flow and glomerular filtration rate (GFR). 1· 4· 16· 26 In contrast, renal blood flow and GFR are decreased by TxA2 through renal vasoconstrictor' effects. Both thromboxanes and PGI 2 alter platelet function; thromboxanes enhance and PGI2 inhibits platelet aggregation. Menhaden oil contains w-3 PUFA, which compete with arachidonic acid in the production of eicosanoids. Consequently, animals fed menhaden oil have a diminution of the 2-series of eicosanoids normally derived from arachidonic acid. Importantly, the eicosanoid derivatives of w-3 polyunsaturated fatty acids (Fig. 3) are less potent than the usual arachidonic acid derivatives. 1· 4• 16· 26 In particular, thromboxanes derived from w-3 PUFA have little vasoconstrictive, inflammatory, or platelet aggregatory effects. Unlike w-6 and w-3 PUFA, the saturated fatty acids present in animal fat do not serve as precursors for eicosanoid production. Proponents of the Brenner's hypothesis of the hemodynamic causes of progressive renal disease have proposed a causal link between production of the 2-series of prostaglandins and thromboxanes and progressive renal disease.

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ro-6 POLYUNSATURATED FATTY ACIDS

• ARACHIDONIC ACID

PROSTAGLANDIN

THROMBOXANE

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A2

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+

VASODILATION

PLATELET AGGREGATION

INFLAMMATION

VASOCONSTRICTION

ENHANCED GROWTH

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I

PROGRESSIVE RENAL FAILURE

Figure 2. Eicosanoids derived from plant oils (w-6 polyunsaturated fatty acids) are of the 2-series and tend to be proinflammatory, enhance platelet aggregation, and are growth promoting. Some are vasoconstrictive while others are vasodilatory. The proposed result of excess dietary supplementation with w-6 polyunsaturated fatty acids is renal injury from enhanced glomerular hypertrophy, disordered intrarenal blood flow, worsening inflammation, and platelet-induced renal injury.

Manipulations that alter renal production of eicosanoids such as dietary supplementation with menhaden oil, which serves as a precursor to production of the 3-series of prostaglandins and thromboxanes, alter the course of chronic renal disease in laboratory animals. 15, 16, 26 Preliminary studies in our laboratory have shown that a low-fat diet supplemented with fish oil rich in w-3 polyunsaturated fatty acids tends to preserve renal function and structure of dogs with induced renal failure, In contrast, dietary supplementation with safflower oil, a rich source of w-6 polyunsaturated fatty acids or beef tallow, appears to be detrimentaJ.S

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ro-3 POLYUNSATURATED FATTY ACIDS

r EICOSAPENTAENOIC ACID

PROSTAGLANDIN

THROMBOXANE

E3

A3

+

+

INHIBITION OF

VASODILATION

PLATELET AGGREGATION J

? PRESERVATION OF RENAL FUNCTION

Figure 3. Eicosanoids derived from w-3 polyunsaturated fatty acids are of the 3-series and are less potent, noninflammatory, vasodilatory, and inhibit platelet aggregation. Theoreti~ cally, supplementation with w-3 polyunsaturated fatty acids could slow the rate of renal injury.

SYSTEMIC HYPERTENSION AND PROGRESSIVE RENAL INJURY

Frequently, dogs and cats with chronic renal failure show elevations of systemic arterial pressure. 1• 15• 16• 19 Systemic hypertension can lead to renal injury in rats. 2 The mechanism of renal injury in systemic hypertension involves both direct effects of blood pressure elevation and an indirect effect due to transmission of high pressures to the glomerular capillary bed. Because of preglomerular vasodilation, 6• 9 cats and dogs with renal disease are susceptible to hypertensive renal injury whenever blood pressure is elevated. Further, diseased canine 10

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(and presumably feline) kidneys lack normal control of preglomerular vessels, allowing even transient elevations of systemic arterial pressure to be transmitted directly to the susceptible glomerular capillary bed. DIETARY FATTY ACID SUPPLEMENTATION AND SYSTEMIC HYPERTENSION

Recent studies in people with renal disease indicate that dietary supplementation with w-3 polyunsaturated fatty acids may lower systemic arterial pressure.24 This could prove an effective therapy in dogs and cats with renal failure and systemic hypertension. Results of ongoing trials are inconclusive at this time. DIETARY FATTY ACIDS AND HYPERLIPIDEMIA

Abnormalities of lipid metabolism in renal disease have been characterized in humans 21 and dogs, 5• 7 and generally include elevated serum levels of total cholesterol, lower density lipoproteins, and triglycerides. Support for an adverse effect of diets enriched with saturated fatty acids was derived from experiments in rats. 21 Lipids (triglycerides, cholesterol, and/or some classes of lipoproteins) stimulate glomerular mesangial cell proliferation and production of excess mesangial matrix, a process referred to as glomerulosclerosis. 21 Uremic renal failure has also be~n causally linked to hyperlipidemia in rats.1· 15· 16 Whereas diets rich in saturated fatty acids raise serum cholesterol and triglyceride concentrations in laboratory animals with renal failure, enhancing diets with PUFA lowers plasma lipid concentrations.1· 15 Previous studies in our laboratory have established an association between hyperlipidemia and renal failure in dogs. 7 Loss of renal function in dogs with experimental renal disease was directly related to plasma triglyceride and total cholesterol concentrations. Preliminary studies in our laboratory have established that cats and dogs with induced renal dysfunction show hypercholesterolemia5 and that the hyperlipidemia can be modified by changes in dietary fatty acid composition. Specifically, animals fed a diet enriched with PUFA (safflower oil or menhaden oil) showed an amelioration of hyperlipidemia compared to dogs fed a diet containing predominantly saturated fatty acids. Similar results have been observed in preliminary studies in cats. The long-term effects of hyperlipidemia on renal function in dogs and cats remain to be established. DIETARY FATTY ACIDS AND PLATELETS AND INFLAMMATION

Investigators have reported that selective thromboxane synthase inhibition can preserve renal structure and/or function in dogs. 18 Though they have a variety of effects, selective thromboxane synthase antagonists are inhibitors of both platelet function and inflammation, which likely contribute to the protective effect in the kidney. Another therapy that limits generation of functional thromboxanes is ingestion of a diet enriched with menhaden oil (w-3 PUFA). Compared to the usual proaggregatory eicosanoid (TxA2), thromboxanes derived from w-3 PUFA (TxA3 ) only weakly facilitate platelet aggregation and eicosanoids derived from w-3 PUFA do not support inflammatory processes.

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DOCUMENT PRESENCE OF CHRONIC RENAL FAILURE

OBTAIN BASELINE VALUES FOR BLOOD PRESSURE, URINE PROTEIN-TO-CREATININE RATIO, AND SERUM CREATININE

SUPPLEMENT DIET WITH 1-5 GRAMS OF 0>-3POLYUNSATURATED FATTY ACID PER DAY

RE-EVALUATE BLOOD PRESSURE, URINE PROTEIN-TO-CREATININE RATIO, AND SERUM CREATININE AT 2 & 4 WEEKS; MONTHLY THEREAFTER FOR 6 MONTHS

ESTIMATE NET EFFECT

+

?

•

,,

CONTINUE

CONSIDER

SUPPLEMENT;

INCREASING

RE-EVALUATE

DOSE

DISCONTINUE SUPPLEMENT

Figure 4. Protocol for therapeutic trial of dietary supplementation with w-3 polyunsaturated fatty acids in dogs. See text for details.

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RENAL DISEASE AND DIETARY FATS: CLINICAL RECOMMENDATIONS

Unfortunately, studies of the effects of variations in dietary fatty acid composition in cats with renal disease are in progress and no clear benefit or adverse effect has yet been identified. Consequently, in part because of their unusual fatty acid metabolic pathways, therapeutic efforts to adjust dietary fatty acid composition for affected cats cannot be justified at this time. Preliminary evidence from recent studies in our laboratory suggests that feeding dogs a menhaden oil-enriched diet slows progressive renal disease. 5 However, the w-6:w-3 ratios of the diets in our study were less than 0.2:1-a ratio that is difficult to achieve in commercially available preparations. The key issue yet to be resolved is the ideal ratio for diets with dogs with renal failure. In the interim, a dietary w-6:w-3 ratio in the range of 5:1 to 15:1 seems a desirable goal. Manufacturers have begun to analyze and supply veterinarians with information pertaining to dietary fatty acid composition and seeking a diet in this range is appropriate. Alternatively, any diet can be supplemented with products that supply. w-3 PUFA, commonly available over the counter (e.g., health food stores). The veterinary fatty acid supplements, which contain a mixture of w-3 and w-6 PUFA, have not been studied in dogs or cats with renal disease and cannot be recommended at this time. Results of our studies indicate that w-6 PUFA supplements should be avoided. Baseline values for mean arterial pressure, the urine protein-to-creatinine ratio, and serum creatinine concentration should be obtained before instituting dietary w-3 PUFA supplementation (Fig. 4). A supplement of 1 to 5 g of w-3 PUFA per day is a reasonable starting dose. Based on studies in our laboratory, 2 to 4 weeks are required to see initial effects of changes in dietary w-6:w-3 ratios. Accordingly, all parameters should be reevaluated at 2 and 4 weeks and then monthly for 6 months. Therapy should be discontinued if an adverse effect is observed at any time. If therapy is continued because of the apparent presence of beneficial effects, the dog should be reevaluated every 3 to 6 months.

References 1. Barcelli UO, Pollack VE: Is there a role for polyunsaturated fatty acids in the prevention of renal disease and renal failure? Nephron 41:209, 1985 2. Bidani A, Mitchell K, Schwartz MM, et a!: Absence of glomerular injury or nephron loss in a normotensive rat remnant kidney model. Kidney lnt 38:28, 1990 3. Brenner BM, Meyer TW, Hostetter TH: Dietary protein intake and the progressive nature of renal disease. N Eng! J Med 307:652, 1982 4. Brown S: Effects of nonsteroidal anti-inflammatory agents on canine renal function. In Kirk RW (ed): Current Veterinary Therapy, vol 10. Philadelphia, WB Saunders, 1989, p 1158 5. Brown S, Brown C, Crowell W, et a!: Effects of dietary lipids on chronic renal disease in the dog and cat. Morris Animal Foundation, 1989-1996 6. Brown SA, Pineo DR, Crowell WA, et a!: Single nephron adaptations to partial renal ablation in the dog. Am J Physiol 258:F495, 1990 7. BrownS, Crowell WA, Barsanti JA, et a!: Beneficial effects of dietary mineral restriction in dogs with 15/16 nephrectomy. JAm Soc Nephrol 1:1169, 1991 8. Brown SA, Walton C, Crawford P, eta!: Long-term effects of antihypertensive regimens on renal hemodynamics and proteinuria in diabetic dogs. Kidney Int 43:1210, 1993 9. Brown SA, Brown CA: Single-nephron adaptations to partial renal ablation in cats. Am J Physiol 269:R1002, 1995

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10. BrownS, Pineo D, Navar L: Impaired renal autoregulatory ability in dogs with reduced renal mass. J Am Soc Nephrol 5:1768, 1995 11. Cowgill LD, Kallet AJ: Recognition and management of hypertension in the dog. In Kirk RW (ed): Current Veterinary Therapy VIII. Philadelphia, WB Saunders, 1983, p 1025 12. DiBartola SP, Rutgers HC, Zack PM, et a!: Clinicopathological findings associated with chronic renal disease in cats: 74 cases. JAm Vet Med Assoc 190:1196, 1987 13. Fries JWU, Sandstrom DJ, Meyer TW, et a!: Glomerular hypertrophy and epithelial cell injury modulate progressive glomerulosclerosis in the rat. Lab Invest 60:205, 1989 14. Gaber L, Walton C, BrownS, eta!: Effects of antihypertensive agents on the morphologic progression of diabetic nephropathy in dogs. Kidney Int 46:161, 1994 15. Heifets M, Morrissey JJ, Purkerson ML, et a!: Effect of dietary lipids on renal function in rats with subtotal nephrectomy. Kidney Int 32:335, 1987 16. Keane WF, Kasiske BL, O'Donnell MP: Hyperlipidemia and the progression of renal disease. Am J Clin Nutr 47:157, 1988 17. Littman MP: Spontaneous systemic hypertension in 24 cats. J Vet Intern Med 8:79, 1994 18. Longhofer SL, Frisbie DD, Johnson HC, et a!: Effects of thromboxane synthetase inhibition on immune complex glomerulonephritis. Am J Vet Res 52:480, 1991 19. MacDonald ML, Rogers QR, Morris JG: Effects of dietary arachidonate deficiency on the aggregation of cat platelets. Comp Biochem Physiol [A] 78:123, 1984 20. MacDonald ML, Anderson BC, Rogers QR, et a!: Essential fatty acid requirements of cats: Pathology of essential fatty acid deficiency. Am J Vet Res 45:1310, 1984 21. Moorhead JF, Chan MK, Varghese Z: The role of abnormalities of lipid metabolism in the progression of renal disease. In Mitch WE (ed): The Progressive Nature of Renal Disease. New York, Churchill Livingstone, 1986, p 133 22. Morgan RV: Systemic hypertension in four cats: Ocular and medical findings. Am An1m Hosp Assoc 22:615, 1986 23. Polzin DJ, Osborne CA: Update: Conservative medical management of chronic renal failure. In Kirk RW (ed): Current Veterinary Therapy IX. Philadelphia, WB Saunders, 1986, p 1167 24. Radack K, Huster G: The effects of low doses of n-3 fatty acid supplementation on blood pressure in hypertensive subjects: A randomized controlled trial. Arch Intern Med 151:1173, 1991 25. Ross LA: Hypertensive diseases. In Ettinger S (ed): Textbook of Veterinary Internal Medicine. Philadelphia, WB Saunders, 1989, p 2047 26. Scharschmidt LA, Gibbons NB, McGarry L, et al: Effects of dietary fish oil on renal insufficiency in rats with subtotal nephrectomy. Kidney Int 32:700, 1987

Address reprint requests to Scott A. Brown, VMD, PhD Department of Physiology and Pharmacology College of Veterinary Medicine University of Georgia· Athens, GA 30602